Date of Award

1983

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Abstract

The pulmonary dynamics, pharamacokinetics and receptor binding of 3-methylindole (3MI) were determined in Equidae. Changes in pulmonary dynamics for the 10 and 20 mg/kg body weight dosages of 3MI from 0 to 48 hours after dosing were determined by whole body plethysmography. Parameters for respiratory rate, minute volume, thoracic gas volume, expiratory/inspiratory time ratio, thoracic gas volume, inspiratory and expiratory flow, and expiratory airway resistance were not significantly different from the time 0 control reading. Pooled means of tidal volume increased significantly (P < 0.05) at 6, 8 and 10 hours after dosing. Significant increases (P < 0.05) in inspiratory airway resistance were observed at the 6, 10, 24 and 48 hour readings. These changes were beginning to reverse within 48 hours after dosing. The pharmacokinetics plasma-concentration profiles for 3MI (10 and 20 mg/kg) in horses were best represented by a two-compartment open model with first order absorption as determined by non-linear least squares regression analysis. Absorption of 3MI at both dosages was rapid. Determinations of the post-distribution half life, total clearance, and area-under-curve of the plasma-concentration profile suggested the presence of non-linear or dose-dependent kinetics for 3MI in horses. Analysis of the structure activity relationships of 3MI and some of its known metabolites suggest that these compounds may bind muscarinic receptors in the lung. {('3)H}-QNB (quinudidinyl benzylate) binds to membranes of rate lung, pony lung and rat brain in a manner indicating selective interaction with a muscarinic receptor. Pharmacological potencies of various muscarinic antagonists and agonists as determined by drug inhibition curves in the presence of 100uM {('3)H}-QNB resembled those observed for other tissues. 3MI and its metabolite ortho-aminoacetophenone (OAAP) were observed to have low potency for binding to muscarinic receptors. From these data, it appears that 3MI and OAAP may interact at either a peripheral site on the receptor macromolecule or affect membrane associated components of the receptor site. These interactions may be the cause of the increased level of bronchomotor tone and resulting increased airway resistance observed in horses after administration of 3MI.

Pages

203

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